Orexin-A, an hypothalamic peptide with analgesic properties

Abstract

The hypothalamic peptide orexin-A and the orexin-1 receptor are localized in areas of the brain and spinal cord associated with nociceptive processing. In the present study, localization was confirmed in the spinal cord and demonstrated in the dorsal root ganglion for both orexin-A and the orexin-1 receptor. The link with nociception was extended when orexin-A was shown to be analgesic when given i.v. but not s.c. in mouse and rat models of nociception and hyperalgesia. The efficacy of orexin-A was similar to that of morphine in the 50 degrees C hotplate test and the carrageenan-induced thermal hyperalgesia test. However, involvement of the opiate system in these effects was ruled out as they were blocked by the orexin-1 receptor antagonist SB-334867 but not naloxone. Orexin-1 receptor antagonists had no effect in acute nociceptive tests but under particular inflammatory conditions were pro-hyperalgesic, suggesting a tonic inhibitory orexin drive in these circumstances. These data demonstrate that the orexinergic system has a potential role in the modulation of nociceptive transmission.

Cardiovascular effects of hypocretin-1 in nucleus of the solitary tract

“…On the other hand, the Hcrt projections to the NTS may function to modulate the activity of visceral afferents and/or to provide a general activation of the parasympathetic system during the digestive and absorptive phases of ingestion. However, it is now clear that orexin systems are not only involved in ingestive behaviors, but also exert an effect on a variety of physiological mechanisms involved in homeostasis (3,13,19,21,23,25,42,44,45,48). Therefore, it is possible that orexigenic pathways may function to adjust cardiovascular responses to activation of these different homeostatic mechanisms (10,12,15,33,42).…”

“…Although both Hcrt-1 and -2 have been shown to have similar physiological effects when administered centrally, Hcrt-1 appears to exert a more potent effect on most of these physiological variables (10,12,33,42,47). Hcrt-1 injections into the brain have been shown to increase feeding and drinking behaviors; produce sleep, wakefulness, and arousal disturbances; produce analgesia; activate the hypothalamic-pituitary axis; elicit gastric acid secretion; and alter temperature regulating mechanisms (3,14,19,21,23,25,42,44,45,48). Hcrt-1 neurons have been shown to contribute to an extensive innervation of forebrain, brain stem, and spinal cord structures (10,33,42,46,47), and receptors to Hcrt-1 have been demonstrated throughout the neuraxis (28).…”

Reciprocal synaptic relationships between orexin- and melanin-concentrating hormone-containing neurons in the rat lateral hypothalamus: a novel circuit implicated in feeding regulation

“…17 Orexin -MCH synaptic interactions in feeding regulation To date, it has been demonstrated that ORX is involved in many physiological phenomena including food intake, 27 -30 sleep, 31 -33 endocrine function, 34 -37 narcolepsy 38,39 and regulation of body temperature, 40 muscle tone 41 and even pain sensation. 42 Likewise, MCH has been shown to play a role in food intake, 5 -7 endocrine function 43 -46 and pigmentation. 47 -49 From these reports, we know that both ORX and MCH play roles in the food intake and endocrine systems.…”

Hypocretin and GABA Interact in the Pontine Reticular Formation to Increase Wakefulness

“…Neuronal systems regulating sleep and wakefulness are anatomically distributed and neurochemically heterogeneous, and the present data suggest that the PnO is one region where hypocretin-1 and GABA interact to increase periods of uninterrupted wakefulness and inhibit sleep. In addition to its wakefulness-promoting actions, hypocretin-1 has antinociceptive effects, 56 which also can be evoked from the PnO. 33 Opioids are the most widely used drugs for the treatment of pain, and negative side effects include disruption of the sleep-wake cycle.…”